Overcoming Resistance to Tumor-Targeted and Immune-Targeted Therapies

Abstract Resistance to anticancer therapies includes primary resistance, usually related to lack of target dependency or presence of additional targets, and secondary resistance, mostly driven by adaptation of the cancer cell to the selection pressure of treatment. Resistance to targeted therapy is frequently acquired, driven by on-target, bypass alterations, or cellular plasticity. Resistance to immunotherapy is often primary, orchestrated by sophisticated tumor–host–microenvironment interactions, but could also occur after initial efficacy, mostly when only partial responses are obtained. Here, we provide an overview of resistance to tumor and immune-targeted therapies and discuss challenges of overcoming resistance, and current and future directions of development. Significance: A better and earlier identification of cancer-resistance mechanisms could avoid the use of ineffective drugs in patients not responding to therapy and provide the rationale for the administration of personalized drug associations. A clear description of the molecular interplayers is a prerequisite to the development of novel and dedicated anticancer drugs. Finally, the implementation of such cancer molecular and immunologic explorations in prospective clinical trials could de-risk the demonstration of more effective anticancer strategies in randomized registration trials, and bring us closer to the promise of cure.